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Canadian Journal of Cardiology

Assessment and Management of Acute Coronary Syndromes (ACS): A Canadian Perspective on Current Guideline-Recommended Treatment – Part 1: Non-ST–Segment Elevation ACS

      Abstract

      Despite the reduction of coronary heart disease mortality over the past 40 years, hospital admissions for acute coronary syndromes (ACS) continue to increase. The goal of this 2-part article is to review the issues at each stage of assessment and management of the ACS patient, and to propose an optimal treatment strategy for the individual patient in the context of the realities, culture, and delivery of healthcare in Canada.
      ACS patients are categorized as either ST segment elevation myocardial infarction (STEMI) or non-ST–elevation ACS (NSTE-ACS). For the patients with NSTE-ACS, prevention of recurrent ischemic events is the primary goal. Assessment of risk for recurrent ischemic and bleeding events helps to determine the net benefit of early cardiac catheterization and percutaneous coronary intervention (PCI) and intensive antiplatelet and anticoagulant treatment. Those with higher ischemic risk features should be considered for an early invasive strategy and receive both dual antiplatelet therapy and an anticoagulant at the time of first medical assessment. Patients without high-risk features could be considered for medical treatment and a selectively invasive strategy; with coronary angiography and revascularization only if high-risk features become apparent.
      Long-term vascular protection with lifestyle modification (especially smoking cessation), lipid lowering, blood pressure and glycemic control, and the use of renin angiotensin aldosterone system (RAAS) blockade to prevent recurrent ischemic events, is important in all patients with ACS.

      Résumé

      En dépit de la diminution de mortalité liée à la maladie coronarienne depuis les 40 dernières années, les admissions à l'hôpital pour des syndromes coronariens aigu (SCA) continuent d'augmenter. Le but de cet article en deux parties est de revoir les enjeux de chacune des étapes de l'évaluation et de la gestion des patients ayant un SCA et de proposer une stratégie de traitement optimal pour un patient donné dans le contexte des réalités, de la culture et des prestations de soins de santé au Canada.
      Les patients ayant un SCA sont catégorisés comme ayant soit un infarctus du myocarde (IM) avec sus-décalage du segment ST ou un SCA sans sus-décalage du segment ST. Pour les patients ayant un SCA sans sus-décalage du segment ST, la prévention d'événements ischémiques récurrents est le principal but. L'évaluation du risque dans les événements ischémiques et hémorragiques récurrents aide à déterminer les avantages de la cathétérisation cardiaque et de l'intervention coronarienne percutanée (ICP) précoces et du traitement intensif par des agents anticoagulants et antiplaquettaires. Ceux ayant des marqueurs de risque ischémique élevé devraient être retenus pour une stratégie invasive précoce et recevoir la bithérapie antiplaquettaire et un anticoagulant au moment de la première évaluation médicale. Les patients n'ayant pas de marqueurs de risque élevés pourraient être retenus pour un traitement médical et une stratégie invasive sélective, en plus d'une angiographie coronarienne et une revascularisation dans le cas où des marqueurs de risque élevé deviendraient apparents.
      La protection vasculaire à long terme dont une modification du style de vie (particulièrement la désaccoutumance au tabac), une diminution des lipides, un contrôle de la pression artérielle et de la glycémie, et l'utilisation d'un blocage du système rénine-angiotensine-aldostérone (SRAA) pour prévenir des événements ischémiques récurrents est importante pour tous les patients ayant un SCA.
      Coronary heart disease remains a major cause of mortality and morbidity. Despite a marked reduction in cardiovascular (CV) mortality over the past 40 years, the rates of myocardial infarction (MI) continue to increase. Approximately 70,000 acute myocardial infarction (AMI) occur each year in Canada and some 19,000 Canadians die from this condition.
      • Tu J.V.
      • Austin P.C.
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      Outcomes of acute myocardial infarction in Canada.
      Healthy People 2010
      Heart Disease and Stroke, Vol. 1, Chapter 12, 2011.
      More than half of 30-day MI mortality occurs prior to hospital arrival, mostly within 1 hour of symptom onset.
      Healthy People 2010
      Heart Disease and Stroke, Vol. 1, Chapter 12, 2011.
      About 12% of initial survivors will die in hospital.
      • Tu J.V.
      • Austin P.C.
      • Filate W.A.
      • et al.
      Outcomes of acute myocardial infarction in Canada.
      Furthermore, there is considerable regional variation, with the far north and Atlantic Canada recording a disproportionately higher event rate.
      • Tu J.V.
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      • Filate W.A.
      • et al.
      Outcomes of acute myocardial infarction in Canada.
      Public Health Agency of Canada
      2009 Tracking Heart Disease and Stroke in Canada.
      • Filate W.A.
      • Johansen H.L.
      • Kennedy C.C.
      • Tu J.V.
      Regional variations in cardiovascular mortality in Canada.
      This regional variation in mortality, in turn, likely reflects the differential distribution of CV risk across the country.
      • Tanuseputro P.
      • Manuel D.G.
      • Leung M.
      • Nguyen K.
      • Johansen H.
      Risk factors for cardiovascular disease in Canada.
      Canadian Community Health Survey 2007/2008, age 12+ except for weight which is age 18+.
      The assessment and management of acute coronary syndromes (ACS) has evolved over the past 35 years due to a wealth of knowledge gained from basic research, clinical trials, registry data, and clinical expertise leading to the development of new technologies. Consequent to improved risk factor modification and management innovations, both short- and longer-term mortality from ACS have fallen substantially. In Ontario, age-adjusted coronary heart disease mortality fell by 35% between 1994 and 2005, with trends in risk factors and improvements in medical management, each explaining about half of the decrease.
      • Wijeysundera H.C.
      • Machado M.
      • Farahati F.
      • et al.
      Association of temporal trends in risk factors and treatment uptake with coronary heart disease mortality, 1994-2005.
      Canadian hospital admissions for MI decreased by 9%-30% between 1994 and 2004, and age-adjusted mortality fell by one-third.
      • Tu J.V.
      • Nardi L.
      • Fang J.
      • Liu J.
      • Khalid L.
      • Johansen H.
      National trends in rates of death and hospital admissions related to acute myocardial infarction, heart failure and stroke, 1994-2004.
      • Ko D.T.
      • Newman A.M.
      • Alter D.A.
      • et al.
      Secular trends in acute coronary syndrome hospitalization from 1994 to 2005.
      The ACS spectrum includes patients with ST-elevation myocardial infarction (STEMI) and non-ST–elevation ACS (NSTE-ACS), which is comprised of non-STEMI (NSTEMI) and unstable angina. The initial difference in pathophysiology and early outcomes between STEMI and NSTE-ACS lead to contrasting early treatment strategies. In STEMI, prompt reopening of the occluded artery is the therapeutic priority that limits the extent of myocardial injury and saves lives (see Part 2 article
      • Fitchett D.H.
      • Theroux P.
      • Brophy J.M.
      • et al.
      Assessment and management of acute coronary syndromes (ACS): a Canadian perspective on current guideline-recommended treatment – part 2: ST-segment elevation myocardial infarction.
      ). In contrast, the therapeutic goals in NSTE-ACS management are to prevent progression of the thrombus to total occlusion, plaque thromboembolization, and recurrent infarction. In-hospital mortality rates in STEMI remain 50% higher than for NSTEMI patients. However, the high rates of recurrent ischemic events in NSTE-ACS patients result in similar 1-year mortality rates in the 2 conditions, emphasizing the need for selecting appropriate early management strategies and secondary prevention measures.
      Older data have suggested suboptimal use of certain acute treatments for STEMI across Canada including, again, some interregional variation.
      • Ko D.T.
      • Newman A.M.
      • Alter D.A.
      • et al.
      Secular trends in acute coronary syndrome hospitalization from 1994 to 2005.
      • Jackevicius C.A.
      • Alter D.
      • Cox J.
      • et al.
      Acute treatment of myocardial infarction in Canada 1999-2002.
      Comparable data for NSTE-ACS are not available but similar variation in care doubtless exists with this condition as well. More remarkable have been the differences noted across provinces in secondary prevention following hospitalization for the index MI, regardless of type
      • Pilote L.
      • Beck C.A.
      • Karp I.
      • et al.
      Secondary prevention after acute myocardial infarction in four Canadian provinces, 1997-2000.
      as well as the differential access to invasive cardiac procedures after an acute MI.
      • Pilote L.
      • Merrett P.
      • Karp I.
      • et al.
      Cardiac procedures after an acute myocardial infarction across nine Canadian provinces.
      Not only do treatment patterns for ACS differ across the country, and on the whole remain somewhat suboptimal,
      • Yan A.T.
      • Yan R.T.
      • Tan M.
      • et al.
      In-hospital revascularization and one-year outcome of acute coronary syndrome patients stratified by the GRACE risk score.
      • Yan A.T.
      • Yan R.T.
      • Tan M.
      • et al.
      Risk scores for risk stratification in acute coronary syndromes: useful but simpler is not necessarily better.
      • Yan R.T.
      • Yan A.T.
      • Tan M.
      • et al.
      Underuse of evidence-based treatment partly explains the worse clinical outcome in diabetic patients with acute coronary syndromes.
      • Yan R.T.
      • Yan A.T.
      • Tan M.
      • et al.
      Age-related differences in the management and outcome of patients with acute coronary syndromes.
      but varying provincial health policies lead to regional differences in treatment access in general.
      • LeLorier J.
      • Bell A.
      • Bougher D.J.
      • Cox J.L.
      • Turpie A.G.
      Drug reimbursement policies in Canada--need for improved access to critical therapies.
      • Guertin J.R.
      • Jackevicius C.A.
      • Cox J.L.
      • et al.
      The potential economic impact of restricted access to angiotensin-receptor blockers.
      • Demers V.
      • Melo M.
      • Jackevicius C.
      • et al.
      Comparison of provincial prescription drug plans and the impact on patients' annual drug expenditures.
      These policies have directly impacted the timing of initiation and duration of coverage of certain key ACS drugs with adverse impact on patient outcomes.
      • LeLorier J.
      • Bell A.
      • Bougher D.J.
      • Cox J.L.
      • Turpie A.G.
      Drug reimbursement policies in Canada--need for improved access to critical therapies.
      • Sheehy O.
      • LeLorier J.
      • Rinfret S.
      Restrictive access to clopidogrel and mortality following coronary stent implantation.
      • Jackevicius C.A.
      • Tu J.V.
      • Demers V.
      • et al.
      Cardiovascular outcomes after a change in prescription policy for clopidogrel.
      The closer the adherence to guideline recommendations for treatment of ACS, the better are clinical outcomes.
      • Peterson E.D.
      • Roe M.T.
      • Mulgund J.
      • et al.
      Association between hospital process performance and outcomes among patients with acute coronary syndromes.
      However, the leading unstable angina/NSTEMI treatment guidelines of the American Heart Association (AHA)/American College of Cardiology (ACC)
      • Anderson J.L.
      • Adams C.D.
      • Antman E.M.
      • et al.
      ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction- executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      with 2011 focused update,
      • Wright S.A.
      • Anderson J.L.
      • Adams C.D.
      • et al.
      2011 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction (updating the 2007 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      and the European Society of Cardiology (ESC)
      • Bassand J.P.
      • Hamm C.W.
      • Ardissino D.
      • et al.
      Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes.
      are comprehensive but complex, and perhaps as a result they often are not followed.
      • Roe M.T.
      • Peterson E.D.
      • Newby L.K.
      • et al.
      The influence of risk status on guideline adherence for patients with non-ST-segment elevation acute coronary syndromes.
      There is no single recipe for all patients, nor does one algorithm fit the requirements of all communities and their populations. Yet a clear and more easily applied set of guideline recommendations is likely to result in a larger proportion of patients receiving optimal recommended treatment. Indeed, it is hoped that at some time in the near future standard approaches to treatment, including the timing of access to investigations and invasive procedures, might be adopted across Canada in order to attenuate the variation in management and potentially the differences in outcome that have been previously documented on a regional basis.
      The goal of this report is to review the issues at each stage of assessment and management of the ACS patient, from presentation to long-term care, and to identify optimal treatment for the individual patient in the context of the realities, culture, and delivery of healthcare in Canada based upon guideline recommendations from the AHA/ACC,
      • Anderson J.L.
      • Adams C.D.
      • Antman E.M.
      • et al.
      ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction- executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      • Wright S.A.
      • Anderson J.L.
      • Adams C.D.
      • et al.
      2011 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction (updating the 2007 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      ESC,
      • Bassand J.P.
      • Hamm C.W.
      • Ardissino D.
      • et al.
      Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes.
      and the recent Canadian Cardiovascular Society Antiplatelet Guideline in the outpatient setting.
      • Bell A.D.
      • Roussin A.
      • Cartier R.
      • et al.
      The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society guidelines.
      In addition, it provides an algorithm for ACS risk assessment and management that is potentially simple to follow and easy to implement.
      The target audience is all health-care professionals involved in the assessment and management of patients with ACS from the time of first medical contact through hospital discharge to long-term care. The secondary prevention measures initiated during hospitalization and continued from the time of hospital discharge will be of interest to primary care physicians. This position paper is not intended as a guide for interventional cardiologists on the technical aspects of percutaneous coronary intervention (PCI) performance in patients with ACS.

      Assessment and Diagnosis

      Assessment begins at first contact with medical services, which is the emergency medical systems about 30%-50% of the time. Patients with persisting symptoms consistent with ischemia (ie, chest pain and/or discomfort, dyspnea) should be encouraged to call an ambulance. When possible, emergency medical systems teams should obtain a 12-lead electrocardiogram (ECG) to identify the presence of ST-T deviation; most importantly to recognize ST-segment elevation promptly in order to facilitate immediate access to timely reperfusion.
      Patients arriving at an emergency department with chest discomfort or other symptoms suggestive of ACS (Table 1) should receive high priority at triage, and undergo a rapid yet comprehensive evaluation of their demographics, past medical history, medications, symptoms, and signs. An ECG should be taken and evaluated within 10 minutes of arrival. Continuous ECG monitoring and an adequate intravenous access should be initiated. Immediate treatment should include aspirin (ASA) 162-325 mg chewed, sublingual nitroglycerin spray (for ongoing symptoms without hypotension or recent use of a phosphodiesterase inhibitor), supplemental oxygen when hypoxic or dyspneic, and morphine for pain control. Other conditions in the differential diagnosis should be considered (Table 2) as well as other medical conditions that could indirectly precipitate a secondary form of accelerated angina such as severe anemia, thyrotoxicosis, or tachyarrhythmia.
      Table 1Signs and symptoms of ACS
      Chest pain or discomfort
       • Central or substernal, upper abdominal, or epigastric discomfort
       • Pain radiating to neck, jaw, shoulders, back, 1 or both arms
       • Sensation of pressure, crushing, tightness, heaviness, cramping, burning, aching
       • Accompanying dyspnea, indigestion, nausea, vomiting, diaphoresis
       • Associated hypotension or ventricular arrhythmias
      Other symptoms associated with myocardial ischemia
       • Isolated dyspnea
       • Weakness
       • Diaphoresis
       • Light-headedness and/or syncope
       • Nausea
       • The elderly, women, and individuals with diabetes may present with ‘anginal equivalents’ or symptoms that are not typical for myocardial ischemia. This occurs in approximately 30% of ACS patients and is associated with a worse prognosis
      • Canto J.G.
      • Shlipak M.G.
      • Rogers W.J.
      • et al.
      Prevalence, clinical characteristics, and mortality among patients with myocardial infarction presenting without chest pain.
      Symptoms of clinical instability
       • Progressive angina (ie, new onset angina with progressive symptoms or exacerbation of pervious angina with more frequent, severe, or prolonged pain occurring at a lower exercise threshold or at rest)
       • Prolonged chest pain (ie, ≥ 20 minutes)
      ACS, acute coronary syndromes.
      Table 2Other conditions to consider in the patient with a suspected acute coronary syndrome
      • Aortic dissection
      • Pulmonary embolism
      • Pneumothorax
      • Pericarditis
      • Esophageal rupture
      • Pneumonia
      • Pancreatitis
      • Cholecystitis
      • Peptic ulcer with or without perforation
      • Gastroesophageal reflux
      The initial ECG is crucial for immediate triage. In the presence of ST-segment elevation or new or presumably new left bundle branch block, immediate reperfusion with either fibrinolysis or primary PCI should be considered (see Part 2 article
      • Fitchett D.H.
      • Theroux P.
      • Brophy J.M.
      • et al.
      Assessment and management of acute coronary syndromes (ACS): a Canadian perspective on current guideline-recommended treatment – part 2: ST-segment elevation myocardial infarction.
      ). Consequently, it is important that the earliest medical contact, including emergency ambulance services, has the ability to record and interpret or transmit ECGs in order to triage patients rapidly to the most appropriate care. Other ECG abnormalities such as ST-segment depression or deep T wave inversion indicate a higher risk NSTE-ACS and support an early invasive management strategy together with dual antiplatelet therapy and parenteral anticoagulation.
      A rise and fall of troponin, in association with symptoms compatible with ACS is associated with an increased risk of recurrent ischemic and fatal events. If the first troponin is below the reference threshold, the test should be repeated 6 hours later. The universal definition of MI requires the detection of a rise and/or fall of a cardiac biomarker with at least 1 value above the 99th percentile reference level (at this level the assay has a coefficient of variation of less than 10%), accompanied by 1 of the following: symptoms consistent with ischemia, ECG changes indicative of new ischemia, new pathological Q waves, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormalities.
      • Thygesen K.
      • Alpert J.S.
      • White H.D.
      Universal definition of myocardial infarction.
      Troponin levels can remain elevated for 10-14 days after ACS; thus elevated levels within 2 weeks of an ACS may not be due to a new event. Extension of an infarction may then be best recognized by a new elevation in CK-MB levels.
      With the development of ultrasensitive troponin assays, the diagnosis of ACS is being made earlier and more frequently.
      • Keller T.
      • Zeller T.
      • Peetz D.
      • et al.
      Sensitive troponin I assay in early diagnosis of acute myocardial infarction.
      Whether a diagnosis of MI should apply to patients with ACS and a rise and fall of troponin to above the very low reference threshold of the ultrasensitive assay, remains controversial and requires further study. Regardless, such individuals do have an increased risk of recurrent ischemic events
      • Keller T.
      • Zeller T.
      • Peetz D.
      • et al.
      Sensitive troponin I assay in early diagnosis of acute myocardial infarction.
      and need long-term measures to reduce further events (including ASA, statins, and blood pressure control), whether or not they undergo early invasive assessment. Troponin is a highly specific and sensitive marker of myocardial cell injury, but is not a specific marker for plaque rupture, erosion, and/or ulceration and thrombosis precipitating ACS. Indeed, circulating troponin can be increased by many non-ACS causes of cardiomyocyte damage (Table 3). Evaluation of a patient in the emergency department found to have a troponin level above the reference threshold includes assessment of the likelihood of an acute coronary ischemic event based upon the history and ECG findings, vs the likelihood of a non-ACS cause of the increased troponin.
      Table 3Increased troponin is a marker of myocardial necrosis, but not necessarily a consequence of an ACS
      ACSCardiac but non-ACSIatrogenicAnalytical
      Myocardial infarction
      • Myocarditis
      • Pulmonary emboli
      • Pulmonary hypertension
      • Heart failure
      • Supraventricular tachycardia
      • Subarachnoid hemorrhage
      • Heart transplant rejection
      • Cardiac contusion
      • Aortic valve disease
      • Renal failure
      • Rhabdomyolysis
      • Pericarditis
      • Cardiac amyloid
      • Scorpion venom
      • Prolonged strenuous exercise
      • Coronary spasm
      • Sepsis
      • Coronary angioplasty
      • Cardiac surgery
      • Balloon valvuloplasty
      • Cardioversion
      • EP ablation
      • Cardiotoxic chemotherapy
      • Heterophile antibodies
      • Rheumatoid factor
      • Fibrin strands
      ACS, acute coronary syndromes; EP, electrophysiology.

      Early Risk Stratification

      Early risk assessment, for both recurrent ischemic events and the risk of bleeding, allows selection of the most appropriate treatment strategy. It is an essential part of the early evaluation of the patient with ACS. Treatments such as an early invasive strategy and anticoagulant and/or antiplatelet agents offer the greatest benefit in the higher risk patient; in contrast, harm from these therapies could outweigh the potential benefits in a low risk patient.
      Clinical observations available at the time of initial evaluation permit an assessment of the risk for recurrent ischemic events (Table 4). The presence of ST-segment depression and elevated troponin levels identify patients at greater risk for recurrent ischemic events. However, even in the absence of ECG abnormalities or elevated biomarkers, patients with typical ischemic cardiac discomfort who have diabetes, renal failure, heart failure, or a history of previous coronary artery bypass graft (CABG), should be carefully evaluated as they may be at high risk for potentially fatal events over the next year.
      • Sanchis J.
      • Bodi V.
      • Nunez J.
      • et al.
      New risk score for patients with acute chest pain, non--ST-segment deviation, and normal troponin concentrations A comparison with the TIMI risk score.
      Outcome after an ACS is determined by an interaction between the patient's pre-event status (eg, age, diabetes, renal function, pre-existing coronary disease, left ventricular function, and prior treatment), and the impact of the acute event (as indicated by low blood pressure, increased heart rate, higher Killip class, ECG ST deviation, and troponin elevation).
      Table 4High-risk features for recurrent ischemic events after NSTE-ACS
      Clinical
       • Multiple episodes of pain (or documented ischemia)
       • Associated heart failure, hypotension, or tachycardia
       • Refractory ischemia with ECG changes despite treatment
       • Renal dysfunction, type 2 diabetes, prior revascularization
      ECG
       • ST-segment depression > 0.5 mm
       • Transient ST-segment elevation
        - Outcome relates to degree of ST depression
       • T-wave inversion > 2 mm in multiple precordial leads
       • New left bundle branch block
       • Sustained ventricular tachycardia
      Biomarker
       • Troponin > 99th percentile reference level (with a troponin test with < 10% variation)
        - Mortality associated with higher levels
        - Lower level increase associated with increased risk for recurrent ischemia and/or MI
      ECG, electrocardiogram; MI, myocardial infarction; NSTE-ACS, non-ST–elevation acute coronary syndromes.
      The initial risk assessment helps to select patients who potentially benefit the most from early cardiac catheterization and intensified antithrombotic therapy. Most clinical trials that compared an early invasive with a conservative strategy selected patients with ECG ST-segment depression and/or an elevated biomarker. However, a wide gradient of risk is known to exist amongst these patients. Consequently, some patients selected either on the basis of an ECG abnormality, or elevated biomarkers may not be truly high risk and hence would not necessarily benefit from an early invasive strategy. Indeed, the 2007 ACC/AHA NSTE-ACS Guidelines
      • Anderson J.L.
      • Adams C.D.
      • Antman E.M.
      • et al.
      ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction- executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      have a grade IIb, evidence level C recommendation for conservative management of initially stabilized patients including some with elevated troponin based on the results of the Invasive vs Conservative Treatment in Unstable Coronary Syndromes (ICTUS) study.
      • de Winter R.J.
      • Windhausen F.
      • Cornel J.H.
      • et al.
      Early invasive versus selectively invasive management for acute coronary syndromes.
      Yet the same guidelines have a grade 1, evidence level A recommendation for an early invasive approach in patients at high risk for recurrent ischemic events identified by factors that include an elevated troponin. In this document we have kept to the ACC/AHA grade 1 recommendation and as indicated in the algorithm, recommend an early invasive approach for most patients with NSTE-ACS and elevated troponin. Furthermore, it should be recognized that some patients who are biomarker-negative may still have a high mortality risk.
      • Steg P.G.
      • FitzGerald G.
      • Fox K.A.
      Risk stratification in non-ST-segment elevation acute coronary syndromes: troponin alone is not enough.
      For this reason, the 2011 ACC/AHA NSTE-ACS guideline update
      • Wright S.A.
      • Anderson J.L.
      • Adams C.D.
      • et al.
      2011 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction (updating the 2007 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      recommend that patients with NSTE-ACS and diabetes, irrespective of troponin status, be considered for an early invasive strategy.
      The application of risk scores such as Thrombolysis in Myocardial Infarction (TIMI)
      • Antman E.M.
      • Cohen M.
      • Bernink P.J.L.M.
      • et al.
      The TIMI risk score for unstable angina / non-ST elevation MI.
      (available at http://www.mdcalc.com/timi-risk-score-for-uanstemi) or Global Registry of Acute Coronary Events (GRACE)
      • Eagle K.A.
      • Lim M.J.
      • Dabbous O.H.
      • et al.
      A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry.
      (available at http://www.outcomes-umassmed.org/grace) may provide a better estimate of benefit from an invasive strategy.
      • Yan A.T.
      • Yan R.T.
      • Tan M.
      • et al.
      Risk scores for risk stratification in acute coronary syndromes: useful but simpler is not necessarily better.
      Although these scores have been validated in other populations, they have never been thoroughly evaluated prospectively. However, despite the perception that they might be cumbersome to routinely use at the bedside, it is clear that the alternative (ie, physician “impression” of risk) is suboptimal in many cases.
      • Yan A.T.
      • Yan R.T.
      • Tan M.
      • et al.
      Risk scores for risk stratification in acute coronary syndromes: useful but simpler is not necessarily better.
      Risk assessment is an ongoing process and must be updated with repeated clinical assessment, ECGs, and troponin levels during the first 12-24 hours.
      • Pelliccia F.
      • Salvini P.
      • Cartoni D.
      • et al.
      Frequency and clinical correlates of changes in thrombolysis in myocardial infarction risk score during observation period at emergency department in “low-risk” patients with acute chest pain.
      Key clinical characteristics to assess include signs or symptoms of recurrent ischemia, heart failure, hemodynamic instability, as well as levels of hemoglobin, electrolytes, blood sugar, and renal function.

      Canadian perspective

      In Canada today, the majority of patients with NSTE-ACS who have either ST depression and or elevated troponin undergo early cardiac catheterization.
      • Zia M.I.
      • Goodman S.G.
      • Peterson E.D.
      • et al.
      Paradoxical use of invasive cardiac procedures for patients with non-ST segment elevation myocardial infarction: an international perspective from the CRUSADE Initiative and the Canadian ACS Registries I and II.
      Most high-risk patients should ideally undergo catheterization within the first 24-48 hours from symptom onset. To ensure the majority of patients at high risk are identified and managed appropriately, a Canadian group published a simplified algorithm of risk stratification
      • Fitchett D.H.
      • Borgundvaag B.
      • Cantor W.
      • et al.
      Non ST segment elevation acute coronary syndromes: a simplified risk-orientated algorithm.
      (Fig. 1) . Patients with symptoms, but no ECG changes or biomarker elevation, are classified as having an indeterminate risk and require observation for at least 12 hours so that their actual risk can be better clarified. Determining the TIMI or GRACE risk score in this indeterminate risk group may also help to direct management, especially related to the need for coronary angiography.
      • Mehta S.R.
      • Granger C.B.
      • Boden W.E.
      • et al.
      Early versus delayed invasive intervention in acute coronary syndromes.
      Early stress testing should be considered in patients with symptoms compatible with myocardial ischemia, but no high risk features.
      Figure thumbnail gr1
      Figure 1Algorithm for management of non-ST–elevation ACS. ACS, acute coronary syndromes; ASA, aspirin; bid, twice daily; BP, blood pressure; ECG, electrocardiogram; IACBP, intra-aortic counterpulsation balloon pump; od, once daily; q, every; SC, subcutaneous; stat, immediately; UFH, unfractionated heparin. *Refers to high-risk features indicated in the shaded rectangle. Refers to high-risk features indicated in the shaded circle.
      Canadian health care providers involved in the management of ACS patients should be aware of the risk-management paradox, with ACS patients at highest risk, as identified by standardized, global risk scores
      • Jedrzkiewicz S.
      • Goodman S.G.
      • Yan R.T.
      • et al.
      Temporal trends in the use of invasive cardiac procedures for non-ST segment elevation acute coronary syndromes according to initial risk stratification.
      • Elbarouni B.
      • Goodman S.G.
      • Yan R.T.
      • et al.
      Validation of the Global Registry of Acute Coronary Event (GRACE) risk score for in-hospital mortality in patients with acute coronary syndrome in Canada.
      being less likely to receive evidence-based, guideline-recommended management.
      • Yan A.T.
      • Yan R.T.
      • Tan M.
      • et al.
      Risk scores for risk stratification in acute coronary syndromes: useful but simpler is not necessarily better.
      • Zia M.I.
      • Goodman S.G.
      • Peterson E.D.
      • et al.
      Paradoxical use of invasive cardiac procedures for patients with non-ST segment elevation myocardial infarction: an international perspective from the CRUSADE Initiative and the Canadian ACS Registries I and II.
      • Yan A.T.
      • Yan R.T.
      • Tan M.
      • et al.
      Management patterns in relation to risk stratification among patients with non-ST elevation acute coronary syndromes.
      Yet this risk paradox is not confined to Canada, as a similar phenomenon has been observed in US
      • Cohen M.G.
      • Filby S.J.
      • Roe M.T.
      • et al.
      The paradoxical use of cardiac catheterization in patients with non-ST-elevation acute coronary syndromes: lessons from the Can Rapid Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC /AHA Guidelines (CRUSADE) Quality Improvement Initiative.
      and European
      • Hasdai D.
      • Behar S.
      • Wallentin L.
      • et al.
      A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin; the Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS).
      studies. In the Canadian ACS Registry II, the most responsible physician was asked to risk stratify individual patients.
      • Yan A.T.
      • Yan R.T.
      • Tan M.
      • et al.
      Risk scores for risk stratification in acute coronary syndromes: useful but simpler is not necessarily better.
      The high-risk group, as determined by the treating physician, had a 3-fold greater mortality compared with low risk individuals, both during the index hospitalization and at 1 year. However, the risk gradient was steeper when patients were stratified by actual risk scores and in multivariable analysis, standardized risk scores were independently associated with 1 year mortality, even after adjusting for risk assessment by physicians. Thus, a risk score consistently provided more prognostic information compared with risk assessment by Canadian physicians.
      In the same study, physicians were asked to provide specific reasons for not recommending certain management options. For patients with NSTE-ACS who were not referred for cardiac catheterization, 68% were considered by their treating physician to be either “not at high enough risk” or that “clinical trial evidence did not support” an early invasive approach. However, 59% of these patients were in fact found to be in a high risk category according to their baseline TIMI Risk Score.
      • Lee C.H.
      • Tan M.
      • Yan A.T.
      • et al.
      Use of cardiac catheterization for non-ST-segment elevation acute coronary syndromes according to initial risk: reasons why physicians choose not to refer their patients.
      Similarly, guideline-indicated medications were sometimes not prescribed during hospitalization and/or at discharge because of the perception that Canadian NSTE-ACS patients were not at high enough risk.
      • Bagnall A.J.
      • Yan A.T.
      • Yan R.T.
      • et al.
      Optimal medical therapy for non-ST-segment-elevation acute coronary syndromes: exploring why physicians do not prescribe evidence-based treatment and why patients discontinue medications after discharge.
      Physicians may believe that they can readily discern and integrate high-risk features into overall risk estimation without the aid of risk scores. However, they may not always recognize and incorporate the most powerful adverse prognosticators (eg, older age) into overall patient risk assessment. With the unique geographic diversity, number, and distribution of tertiary care facilities in Canada, there is a significant opportunity to improve upon accurate risk stratification and facilitate more appropriate tailoring of therapies in Canadian ACS patients.

      Assessing Bleeding Risk

      Although intensive antithrombotic therapy and invasive management reduce recurrent ischemic events, they also increase the risk of bleeding. Major bleeding and the need for transfusion have become the most frequent complication of ACS, and are associated with a 60% higher risk of in-hospital mortality and a 5-fold greater 1-year risk of death or MI.
      • Moscucci M.
      • Fox K.A.
      • Cannon C.P.
      • et al.
      Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE).
      The most frequent bleeding locations are from the gastrointestinal tract and the femoral vascular access site used for coronary angiography.
      Reducing the incidence and impact of major bleeding in patients with ACS requires identification of the patient at high risk for bleeding, selection of management strategies to minimize risk, such as the use of radial arterial access, control of modifiable risk factors, and early recognition and prompt management of bleeding when it does occur.
      Clinical features associated with increased bleeding are shown in Table 5. A bleeding score derived from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) Registry
      • Subherwal S.
      • Bach R.G.
      • Chen A.Y.
      • et al.
      Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) bleeding score.
      (available at http://www.crusadebleedingscore.org), identifies the following as predictors of bleeding: baseline hematocrit, creatinine clearance, heart rate, systolic blood pressure, female gender, presence of heart failure, prior stroke or vascular disease, and diabetes. A history of prior bleeding is a most important predictor of recurrent bleeding, yet this information was not available to the CRUSADE investigators. A bleeding risk score derived from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) and Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trials showed 6 independent baseline variables predicted non-CABG related major bleeding.
      • Mehran R.
      • Pocock S.J.
      • Nikolsky E.
      • et al.
      A risk score to predict bleeding in patients with acute coronary syndromes.
      These were female sex, advanced age, elevated creatinine, elevated white blood cell count, anemia, and a diagnosis of MI rather than unstable angina. A recent analysis of the Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines (ACTION Registry-GWTG) population of both STEMI and NSTE-ACS patients also highlights the importance of age and renal function as important predictors of bleeding.
      • Mathews R.
      • Peterson E.D.
      • Chen A.Y.
      • et al.
      In-hospital major bleeding during ST-elevation and non-ST-elevation myocardial infarction care: derivation and validation of a model from the ACTION registry(R)-GWTG.
      Table 5Clinical factors associated with increased bleeding risk
      Patient factorsManagement factors
      • • Advanced age
      • • Female gender
      • • Low body weight
      • • History of bleeding
      • • Hypertension
      • • Hemodynamic instability
      • • Increased risk of ischemic event
      • • Renal insufficiency (CrCl < 60 mL per min)
      • • Use of glycoprotein IIb/IIIa inhibitors
      • • Catheterization/PCI in first 24 h
      • • Femoral access site
      • • Excessive antiplatelet and/or antithrombotic dosing
      • • Triple therapy (ASA, clopidogrel, and warfarin)
      ASA, aspirin; PCI, percutaneous coronary intervention.
      Because renal dysfunction has a particularly large impact on the risk of bleeding in all these risk scores, it is important to recognize that medications such as enoxaparin and fondaparinux and the small molecule glycoprotein (GP) IIb/IIIa inhibitors (tirofiban or eptifibatide) require dose adjustments according to the estimated glomerular filtration rate (eGFR), and probably should not be used in more severe renal insufficiency. In moderate to severe renal insufficiency (eGFR < 30 mL per min) unfractionated heparin (UFH) is usually the preferred choice. Indeed, careful attention to choice of antithrombotic therapy is warranted in the setting of renal dysfunction, given potentially inappropriate use and/or dosing in routine clinical care,
      • LaPointe N.M.
      • Chen A.Y.
      • Alexander K.P.
      • et al.
      Enoxaparin dosing and associated risk of in-hospital bleeding and death in patients with non ST-segment elevation acute coronary syndromes.
      and the fact that 4 of 10 Canadian NSTE-ACS patients present with moderate to severe renal insufficiency.
      • Wong J.A.
      • Goodman S.G.
      • Yan R.T.
      • et al.
      Temporal management patterns and outcomes of non-ST elevation acute coronary syndromes in patients with kidney dysfunction.
      Reducing the risk of bleeding requires consideration of the predisposing factors and the use of strategies to minimize the potential for blood loss (Table 6). Radial arterial access for coronary angiography and/or PCI decreases the need for blood transfusion by more than 50%.
      • Chase A.J.
      • Fretz E.B.
      • Warburton W.P.
      • et al.
      Association of the arterial access site at angioplasty with transfusion and mortality: the M.O.R.T.A.L study (Mortality benefit Of Reduced Transfusion after percutaneous coronary intervention via the Arm or Leg).
      The recently reported Radial vs Femoral Access for Coronary Angiography or Intervention (RIVAL) trial
      • Jolly S.S.
      • Yusuf S.
      • Cairns J.
      • et al.
      Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial.
      in over 7000 patients with ACS, randomized vascular access to the radial or femoral artery and showed no significant difference in the primary combined outcome of death, MI, stroke, or non-CABG major bleeding. However, major vascular complications (including large hematoma) were less when the radial arterial approach was used. Furthermore, in the STEMI subgroup there was a 40% reduction of the combined primary outcome and a 61% reduction of mortality in the patients who had radial arterial access. In centres with high volume use of radial arterial access, the radial arterial approach was associated with a 51% reduction of the primary combined end point. Smaller sheaths, radial access, and timely sheath removal likely reduce the bleeding risk even when potent antithrombotic and/or antiplatelet therapy is used.
      • Cantor W.J.
      • Mahaffey K.W.
      • Huang Z.
      • et al.
      Bleeding complications in patients with acute coronary syndrome undergoing early invasive management can be reduced with radial access, smaller sheath sizes, and timely sheath removal.
      In high-risk individuals who require anticoagulation for several days, choosing fondaparinux rather than enoxaparin reduces bleeding.
      • Yusuf S.
      • Mehta S.R.
      • et al.
      The Fifth Organisation to Assess Strategies in Acute Ischemic Syndromes Investigators
      Comparison of fondaparinux and enoxaparin in acute coronary syndromes.
      Management of bleeding depends upon the site and severity of bleeding (Table 7).
      Table 6Prevention of bleeding
      • Careful patient history, physical examination, and assignment to therapy
      • Appropriate dosing of antithrombotic drugs (consider age, renal function, weight)
      • Shorten duration of exposure to antithrombotic agents (if early invasive strategy is selected, early catheterization)
      • Use fondaparinux or UFH in patients at higher risk
      • Use a proton pump inhibitor for gastric protection in patients at high risk
      • At the time of angiography/angioplasty radial artery access may be preferred; catheter size should be minimized; sheaths should be removed as soon as possible
      • Respond to bleeding early: reduce medications and consider reversing anticoagulation with high-risk bleed. Identify retroperitoneal bleeding (perform CT scan in patients with back or leg pain, hypotension, or progressive anemia)
      CT, computed tomography; UFH, unfractionated heparin.
      Table 7Management of bleeding
      Local hemostasis when possible
      Minor bleeding
       • Continue anticoagulation if possible
      Major bleeding
       • Discontinue IV anticoagulation, GP IIb/IIIa inhibitor
       • Maintain volume status
       • Avoid transfusion if possible (transfuse only when Hb < 80 g/L or Hct < 25%)
       • Consider platelet transfusion; protamine for UFH/enoxaparin
       • Give Octaplex (prothrombin complex concentrate) if high INR on warfarin
       • rFactor VII only if bleeding is severe, life-threatening
      GP, glycoprotein; Hb, hemoglobin; Hct, hematocrit; INR, international normalized ratio; IV, intravenous; UFH, unfractionated heparin.
      Therapeutic dual oral antiplatelet therapy at the time of major surgery significantly increases bleeding risk. Clopidogrel taken within 5 days of coronary artery bypass surgery is associated with a 50% increase in major bleeding.
      The clopidogrel in unstable angina to prevent recurrent events trial investigators
      effects of clopidogrel in addition to ASA in patients with acute coronay syndromes without ST segment elevation.
      For the 8%-15% of ACS patients that require coronary bypass surgery during the index hospitalization, the majority can wait for 5 days after discontinuation of clopidogrel before undergoing the operation. For prasugrel (which should not be administered in patients with NSTE-ACS until after the coronary artery anatomy has been defined, to conform with the protocol of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel [TRITON] study),
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Prasugrel versus clopidogrel in patients with acute coronary syndromes.
      it is recommended that most patients discontinue the agent 7 days prior to surgery. Small numbers of very high-risk unstable patients require surgery earlier, and they should not be denied life-saving surgery because of an increased bleeding risk. The recently reported analysis of the Platelet Inhibition and Patient Outcomes (PLATO) study suggests that patients undergoing CABG who had received ticagrelor within 7 days of surgery had a lower mortality than the patients receiving clopidogrel, without any increase in perioperative bleeding.
      • Held C.
      • Asenblad N.
      • Bassand J.P.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial.

      Canadian perspective

      The radial arterial approach to coronary arterial procedures is advocated by many Canadian centres and is currently used in an increasing proportion of patients undergoing both coronary angiography and PCI.
      • Bertrand O.F.
      • Rao S.V.
      • Pancholy S.
      • et al.
      Transradial approach for coronary angiography and interventions: results of the first international transradial practice survey.
      Although the recently reported RIVAL trial
      • Jolly S.S.
      • Yusuf S.
      • Cairns J.
      • et al.
      Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial.
      showed no difference for major outcomes in the overall trial, patient preferences, the results with high volume use of the radial access, and the reduced vascular complication rate, favour the radial approach in many Canadian centres.
      Clopidogrel is routinely administered in the emergency department to most patients with NSTE-ACS. For patients requiring urgent CABG who have received clopidogrel, there is a range of practice standards in Canada. Some surgeons delay surgery for at least 5 days, and others operate promptly and use a variety of techniques to minimize bleeding. A consistent approach by cardiac surgeons in assessing the benefits and risks of early surgery has been encouraged by the recent publication of a Canadian position paper.
      • Fitchett D.
      • Eikelboom J.
      • Fremes S.
      • et al.
      Dual antiplatelet therapy in patients requiring urgent coronary artery bypass grafting surgery: a position statement of the Canadian Cardiovascular Society.
      While the Canadian product monograph recommendation for delaying bypass surgery (where possible) in ticagrelor-treated patients is also 5 days, unique properties of this adenosine diphosphate-receptor antagonist (ie, reversible binding with restoration of platelet function as plasma drug levels fall) may allow proceeding to CABG slightly earlier (eg, 72-96 hours after the last dose).

      Selection of Management Strategy

      The choice of either an early invasive strategy (with elective coronary angiography within the first 24-48 hours) or a more conservative selective invasive strategy (with medical treatment and coronary angiography only in response to recurrent symptoms, development of other high-risk clinical features, or high risk noninvasive testing) is made after weighing the balance of expected benefits and risks (Table 8). Consider the risk of complications from an invasive procedure, especially bleeding, as low-risk patients may have limited benefit from an invasive approach, or may even be harmed.
      • Cantor W.J.
      • Goodman S.G.
      • Cannon C.P.
      • et al.
      Early cardiac catheterization is associated with lower mortality only among high-risk patients with ST- and non-ST-elevation acute coronary syndromes: observations from the OPUS-TIMI 16 trial.
      The choice of a selectively invasive approach is reasonable in patients considered to be at lower risk for recurrent ischemic events or in those at higher ischemic risk if the high risk of bleeding or other procedural complications outweigh the potential benefit of the procedure.
      Table 8Advantages and disadvantages of an early invasive management strategy
      AdvantagesDisadvantages
      • • Easy risk stratification approach
      • • Rapid, accurate diagnosis and risk stratification
      •  - Approximately 20% with no angiographically significant CAD
      •  - Approximately 15% with left main stenosis
      • • Improved outcomes from early revascularization in high-risk patients
      • • Complications from invasive procedure (MI, bleeding)
      • • Patients without higher risk features have no prognostic benefit and may delay early intervention for high-risk patients
      • • Cost, impact on resources
      CAD, coronary artery disease; MI, myocardial infarction.
      A meta-analysis
      • Bavry A.A.
      • Kumbhani D.J.
      • Rassi A.N.
      • Bhatt D.L.
      • Askari A.T.
      Benefit of early invasive therapy in acute coronary syndromes: a meta-analysis of contemporary randomized clinical trials.
      of major clinical trials to date comparing an invasive strategy to a selective invasive approach in higher risk NSTE-ACS patients showed that an invasive strategy led to:
      • A significant 25% reduction in mortality over a mean follow-up period of 2 years;
      • An 18% reduction in nonfatal MI over the period of follow-up;
      • A 31% reduction in recurrent unstable angina requiring hospitalization.
      A recent meta-analysis shows that an early invasive strategy in high-risk patients reduces the 5-year absolute risk of death and/or MI by 11%.
      • Fox K.A.
      • Clayton T.C.
      • Damman P.
      • et al.
      Long-term outcome of a routine versus selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome a meta-analysis of individual patient data.
      The clinical trials published between 1994 and 2005 have a wide range of entry criteria, management, and treatment strategies (including time to catheterization and revascularization, mode of revascularization, adjunctive antithrombotic therapy, and definition of ischemic end points) precluding any precise estimate of benefit. However, a common finding is that only the higher-risk patients benefit from the early invasive strategy.
      • Cantor W.J.
      • Goodman S.G.
      • Cannon C.P.
      • et al.
      Early cardiac catheterization is associated with lower mortality only among high-risk patients with ST- and non-ST-elevation acute coronary syndromes: observations from the OPUS-TIMI 16 trial.
      The Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction (TACTICS-TIMI) 18 trial
      • Cannon C.P.
      • Weintraub W.S.
      • Demopoulos L.A.
      • et al.
      Invasive versus conservative strategies in unstable angina and non-Q-wave myocardial infarction following treatment with tirofiban: rationale and study design of the international TACTICS-TIMI 18 Trial Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy. Thrombolysis In Myocardial Infarction.
      indicated the optimal timing of coronary angiography in the ACS patient selected for an invasive strategy was within the first 48 hours. The CRUSADE registry
      • Ryan J.W.
      • Peterson E.D.
      • Chen A.Y.
      • et al.
      Optimal timing of intervention in non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) Registry.
      suggested there was no harm delaying investigation by 1 day in most patients. The Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial
      • Mehta S.R.
      • Granger C.B.
      • Boden W.E.
      • et al.
      Early versus delayed invasive intervention in acute coronary syndromes.
      showed that for the majority of patients with NSTE-ACS early (< 24 hours) coronary angiography was no better than delayed (> 36 hours) investigation. However, for high-risk patients (approximately 30%) with a high GRACE risk score (> 141), early coronary angiography (median 16 hours) resulted in a significantly lower rate of death, MI, or stroke compared with later investigation (median 50 hours). Consequently, the majority of patients with NSTE-ACS selected for an early invasive management strategy can wait 24-72 hours, and only the highest risk should be considered for an early emergent procedure (Table 9).
      Table 9Characteristics in favour and against early invasive strategy: Levels of recommendation
      Grade 1; strong recommendationGrade 2; need to assess benefits and risks in individual patientGrade 3; not recommended
      • • Refractory angina and/or ischemia (1B)
      • • Clinical instability (1B)
      • • Elevated risk for ischemic event (1A)
      • • Chronic renal insufficiency
      • • Diabetes (consider as indication for early invasive strategy)
      • • Competing comorbidities, high risk of revascularization and comorbid conditions outweigh benefits of revascularisation
      • • Acute chest pain with low likelihood of ACS
      • • No patient consent to undergo revascularization whatever the findings
      ACS, acute coronary syndrome.

      Anticoagulant and Antiplatelet Therapy

      Both antiplatelet and anticoagulation therapies are required to reduce thrombotic and recurrent ischemic events in patients with ACS whether or not the patient is destined for an early invasive or selectively invasive strategy.

      Anticoagulation

      Currently available agents are UFH, low molecular weight heparin (usually enoxaparin), fondaparinux, and bivalrudin (see Table 10). The choice of individual agents depends upon the risk of an ischemic event, the management strategy (early invasive vs conservative), the time to cardiac catheterization (very early vs later), renal function, and the bleeding risk. For patients with severe renal dysfunction, enoxaparin, fondaparinux, and bivalrudin are contraindicated.
      • Bassand J.P.
      The place of fondaparinux in the ESC and ACC/AHA guidelines for anticoagulation in patients with non-ST elevation acute coronary syndromes.
      Although enoxaparin prescribing information recommends dose adjustments when eGFR is less than 30mL per minute, there are no safety data to support this strategy. Fondaparinux is renally excreted, but is safer than enoxaparin in patients with creatinine < 265 μmol/L or eGFR > 30mL per minute.
      • Yusuf S.
      • Mehta S.R.
      • et al.
      The Fifth Organisation to Assess Strategies in Acute Ischemic Syndromes Investigators
      Comparison of fondaparinux and enoxaparin in acute coronary syndromes.
      Table 10Anticoagulant properties
      MonitoringCauses HITImpact of renal dysfunction
      UFHFrequent aPTT+++
      Low molecular weight HeparinNone
       Enoxaparin++++
       Dalteparin++++
      FondaparinuxNone+++
      BivalrudinNone+
      + to +++ indicates increasing impact. – indicates no impact.
      aPTT, activated partial thromboplastin time; HIT, heparin-induced thrombosis; UFH, unfractionated heparin.
      Enoxaparin was shown to be superior to UFH in ACS trials when the agents were compared with treatment durations of at least 48-72 hours.
      • Petersen J.L.
      • Mahaffey K.W.
      • Hasselblad V.
      • et al.
      Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-Segment elevation acute coronary syndromes: a systematic overview.
      In the Superior Yield of the New Strategy of Enoxaparin, Revascularisation and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial,
      The Synergy Trial Investigators
      Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy Primary results of the SYNERGY randomized trial.
      enoxaparin in patients managed with very early (median 22 hours) coronary angiography was not superior to UFH for efficacy, but major bleeding was increased. Fondaparinux was compared with enoxaparin in the Organization to Assess Strategies in Ischemic Syndromes (OASIS) 5 trial and was associated with similar early (9-day) ischemic events yet bleeding rates were halved.
      • Yusuf S.
      • Mehta S.R.
      • et al.
      The Fifth Organisation to Assess Strategies in Acute Ischemic Syndromes Investigators
      Comparison of fondaparinux and enoxaparin in acute coronary syndromes.
      By 30 days, there was a significant reduction in mortality in the fondaparinux group that was closely associated with the reduced bleeding. Bivalirudin monotherapy in the ACUITY trial,
      • Stone G.W.
      • McLaurin B.T.
      • Cox D.A.
      • et al.
      Bivalirudin for patients with acute coronary syndromes.
      when compared with UFH or enoxaparin combined with a GP IIb/IIIa inhibitor, showed no reduction of ischemic events yet bleeding was reduced. Interpretation of the ACUITY trial results is confounded by the fact that almost two-thirds of patients receiving enoxaparin or UFH prior to randomization, and then received study drug anticoagulation for only 4-5 hours subsequently. As most NSTE-ACS patients in Canada would require bivalirudin treatment for more than 24 hours prior to catheterization, it is unlikely that bivalirudin would be a cost-effective alternative to either UFH or enoxaparin when administered over this longer time period. Presently, the use of bivalirudin in Canada is confined to patients in the catheterization laboratory undergoing PCI.
      The ESC and AHA/ACC recommendations on the tailored use of anticoagulation differ. Table 11 shows a suggested Canadian approach (that is closer to the ESC recommendations than the US guidelines). The choice of either fondaparinux or enoxaparin depends upon local practice and may be influenced by the opinions of local cardiologists.
      Table 11Suggested antithrombotic approach for the Canadian setting
      Urgent invasive approach
       ASA, ticagrelor (180 mg loading dose) or clopidogrel (600 mg loading dose)
       Consider a GP IIb/IIIa antagonist in patients with refractory symptoms or clinical instability
       Use UFH
      Early invasive approach (within 48 h)
       ASA, ticagrelor (180 mg loading dose followed by 90 mg twice daily; consider additional 90 mg at the time of PCI) or clopidogrel (consider 600 mg loading dose followed by 75 mg daily; consider 150 mg for days 2-7, followed by 75 mg daily in patients undergoing PCI)
       Fondaparinux, enoxaparin, or UFH. If increased bleeding risk consider fondaparinux
      Selectively invasive and/or delayed intervention
       ASA, ticagrelor (180 mg loading dose followed by 90 mg twice daily; consider additional 90 mg at the time of PCI) or clopidogrel (300 mg loading dose followed by 75 mg daily dosing; consider additional 300 mg load at the time of PCI, and 150 mg for days 2-7, followed by 75 mg daily in patients undergoing PCI)
       Fondaparinux preferable to enoxaparin, especially if bleeding risk is high. Continue to hospital discharge
      ASA, aspirin; GP, glycoprotein; PCI, percutaneous coronary intervention; UFH, unfractionated heparin.

      Antiplatelet therapy

      ASA and clopidogrel are currently the antiplatelet agents most frequently used in the early management of ACS. ASA was introduced for the management of ACS in the mid-1980's after 4 trials showed a greater than 50% reduction of death or MI in short- and long-term administration. Yet the optimal dose of ASA remains controversial because until recently, there was no large-scale comparison of ASA dose in ACS. Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events-Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS) 7
      • Mehta S.R.
      • Tanguay J.-F.
      • Eikelboom J.W.
      • et al.
      Double dose versus standard dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial.
      was a Canadian-led, international trial evaluating higher-dose (300-325 mg daily) vs low-dose (75-100 mg daily) ASA following a ≥ 300 mg load in over 25,000 patients with NSTE-ACS and STEMI in a factorial design also comparing optimal clopidogrel dosing.
      • Mehta S.R.
      • Bassand J.P.
      • et al.
      CURRENT-OASIS 7 Investigators
      Dose comparisons of clopidogrel and aspirin in acute coronary syndromes.
      CURRENT demonstrated no difference in 30-day efficacy, major bleeding, or stent thrombosis with higher- compared with lower-dose ASA; however, more gastrointestinal and minor bleeding was observed with higher-dose ASA. Based on these data, low-dose ASA appears to be the best strategy in NSTE-ACS and STEMI patients. Beyond 30 days, there are few randomized data to guide optimal dose and the low-dose ASA remains the near universal choice.
      Dual antiplatelet therapy with ASA and clopidogrel became the standard of care for NSTE-ACS after the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • et al.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      showed that this strategy reduced recurrent ischemic events by a relative 20% compared with ASA alone. The benefit was observed within hours of initiating treatment and increased over the following 90 days. Overall, major bleeding (but not life-threatening bleeding) was increased by an absolute 1% in patients on clopidogrel. Bleeding rates may be influenced by the ASA dose more than the use of clopidogrel.
      • Peters R.J.
      • Mehta S.R.
      • Fox K.A.
      • et al.
      Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study.
      Both the ESC and ACC/AHA guidelines recommend the administration of dual antiplatelet therapy with both ASA (loading dose > 162 mg and maintenance dose 75-100 mg to minimize the risk of bleeding) and clopidogrel to medium- or high-risk patients with NSTE-ACS at the time of presentation.
      The optimal dose of clopidogrel remains controversial. The CURRENT-OASIS 7 trial
      • Mehta S.R.
      • Tanguay J.-F.
      • Eikelboom J.W.
      • et al.
      Double dose versus standard dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial.
      showed that increasing the loading dose of clopidogrel from 300 to 600 mg and using 150 mg daily maintenance dose for the first week (instead of the usual 75 mg) did not reduce the primary outcome of CV death, MI, or stroke at 30 days. In addition, there was a significant increase in major bleeding with the higher dose regimen. In a prespecified, subgroup analysis of patients who underwent PCI, double-dose clopidogrel significantly reduced the rate of the primary outcome and definite stent thrombosis. Despite the benefits observed in the subgroup of patients who underwent PCI after randomization, there was a nonsignificant numeric increase in the primary end point among patients who did not undergo PCI (ie, those who instead underwent CABG or were treated medically). Thus, unless there is a high degree of certainty that the patient will be undergoing PCI (eg, those undergoing primary PCI for STEMI), standard-dose (300 mg) clopidogrel should probably remain as the current regimen employed within the first 24 hours for an ACS patient presenting to the emergency department. Specific recommendations for the use of clopidogrel are shown in Table 12.
      Table 12Recommendations for use of clopidogrel in NSTE-ACS
      Loading dose
       Clopidogrel 300 mg followed by 75 mg daily
       Clopidogrel 600 mg followed by clopidogrel 150 mg daily for 7 d is preferred if likely to undergo urgent or early angiography and PCI
      Reloading
       A reloading dose of 300 mg (or 600 mg) is recommended in patients already using clopidogrel who will likely undergo PCI
      Allergy or intolerance
       Cutaneous rash may develop after PCI in relation with administration of contrast agents and other drugs including clopidogrel. The allergic reaction is treated with antihistaminic drugs and corticosteroids if required. If the rash disappears after 2 to 3 d, clopidogrel is continued; if it persists, clopidogrel is stopped and replaced with an alternative
      Alternative therapy
       Ticlopidine has been the replacement agent for patients who could not tolerate clopidogrel, however, adverse effects and the need for close hematological monitoring make it an unattractive agent today
       Prasugrel is suitable for administration to patients about to undergo PCI in whom the coronary anatomy is known and have not already received clopidogrel. Cross-reactivity with prasugrel is reported in patients with clopidogrel sensitivity
       Ticagrelor is likely the best replacement for patients with clopidogrel allergy
      Duration of therapy
       The ACC/AHA and ESC recommend 12 mo of therapy after ACS, whether in medically treated patients, or those undergoing a revascularization procedure (placement of a drug-eluting- or bare-metal stent)
      ACC, American College of Cardiology; ACS, acute coronary syndromes; AHA, American Heart Association; ESC, European Society of Cardiology; NSTE-ACS, non-ST–elevation ACS; PCI, percutaneous coronary intervention.
      The early use of GP IIb/IIIa inhibitors was shown to reduce recurrent ischemic events in patients with NSTE-ACS in an era prior to the introduction of clopidogrel and when high risk NSTE-ACS patients waited 48-72 hours for coronary angiography.
      • Boersma E.
      • Harrington R.A.
      • Moliterno D.J.
      • et al.
      Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials.
      • Boersma E.
      • Westerhout C.M.
      Intravenous glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: lessons from recently conducted randomized clinical trials.
      For patients undergoing PCI, GP IIb/IIIa inhibitors administered during and after the procedure reduce periprocedural events and improve long-term outcomes. The Early Glycoprotein IIb/IIIa Inhibition in Patients with Non-ST–Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial
      • Giugliano R.P.
      • White J.A.
      • Bode C.
      • et al.
      Early versus delayed, provisional eptifibatide in acute coronary syndromes.
      failed to show benefit from a strategy using upstream eptifibatide routinely in patients with ACS, administered at least 12 hours prior to angiography, compared with the provisional use of the GP IIb/IIIa inhibitor during and after the PCI. Furthermore, significantly higher rates of bleeding and transfusions were reported in the patients receiving up-front treatment. A subsequent analysis
      • Wang T.Y.
      • White J.A.
      • Tricoci P.
      • et al.
      Upstream clopidogrel use and the efficacy and safety of early eptifibatide treatment in patients with acute coronary syndrome: an analysis from the Early Glycoprotein IIb/IIIa Inhibition in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial.
      of EARLY ACS suggested that eptifibatide was only beneficial in patients who had received clopidogrel pretreatment. Similarly, the ACUITY study
      • Stone G.W.
      • Bertrand M.E.
      • Moses J.W.
      • et al.
      Routine upstream initiation vs deferred selective use of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: the ACUITY timing trial.
      showed that the deferred use of the GP IIb/IIIa inhibitor in the catheterization laboratory was associated with significantly fewer bleeding events, but with the same rates of clinical outcomes at 30 days as with the upstream use.
      Consequently, the use of GP IIb/IIIa inhibitors (eptifibatide, tirofiban, and abciximab) should be mainly restricted to those patients undergoing PCI, but could also be considered prior to the procedure (ie, upstream use) in patients with ongoing and/or recurrent ischemia despite dual antiplatelet therapy and an anticoagulant, and those with heart failure, serious arrhythmias, or cardiogenic shock who are scheduled for urgent coronary angiography.

      Alternative antiplatelet agents

      In vitro studies have shown considerable variability of clopidogrel inhibition of platelet aggregation. Recent studies have demonstrated genetic polymorphisms of cytochrome enzymes responsible for clopidogrel metabolism to the active metabolite that are responsible for reduced clopidogrel-induced inhibition of platelet aggregation and an associated increase of ischemic cardiac events in patients with recent ACS.
      • Mega J.L.
      • Close S.L.
      • Wiviott S.D.
      • et al.
      Cytochrome p-450 polymorphisms and response to clopidogrel.
      • Simon T.
      • Verstuyft C.
      • Mary-Krause M.
      • et al.
      Genetic determinants of response to clopidogrel and cardiovascular events.
      Clopidogrel has a slow onset of action and achieves only 50%-60% inhibition of platelet aggregation. However, it is unclear as yet what is the optimal level of platelet inhibition with oral antiplatelet agents for acute and long-term ACS management.
      Two new antiplatelet agents, prasugrel and ticagrelor have recently been approved for use in Canada. Prasugrel is a third generation thienopyridine irreversible platelet P2Y12-receptor inhibitor. Compared with clopidogrel, prasugrel requires 1 rather than 2 metabolic steps to generate the active metabolite, resulting in more rapid, potent, and consistent platelet inhibition, and is not affected by genetic polymorphisms of cytochrome P450 (CYP) enzymes responsible for metabolic activation of clopidogrel (eg, CYP3A5 and CYP2C19).
      • Varenhorst C.
      • James S.
      • Erlinge D.
      • et al.
      Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease.
      In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 study
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Prasugrel versus clopidogrel in patients with acute coronary syndromes.
      of thienopyridine-naive patients with an acute or recent ACS undergoing PCI (and where the coronary anatomy had been defined unless the patient was going to primary PCI for STEMI), prasugrel was shown to be superior to clopidogrel for the reduction of ischemic events and early stent thrombosis. Major bleeding, including fatal bleeding unrelated to CABG surgery, was significantly higher in prasugrel-treated patients. Thus, for Canadian ACS patients with identified coronary anatomy warranting PCI, prasugrel 60 mg administered immediately before PCI, followed by 10 mg daily, offers better protection from recurrent ischemic events (including MI) and stent thrombosis than clopidogrel 300 mg followed by 75 mg daily. The consistency of the observed benefit of prasugrel over clopidogrel was observed in subgroups of patients, such as those with STEMI and with a history of diabetes.
      Current Canadian practice, based on the results of the CURE
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • et al.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      trial, is to administer clopidogrel 300 mg in the emergency department, and not to wait until coronary angiography has been performed.
      • Rao R.V.
      • Goodman S.G.
      • Yan R.T.
      • et al.
      Temporal trends and patterns of early clopidogrel use across the spectrum of acute coronary syndromes.
      The strategy of up-front loading of prasugrel in a medically managed patient population is currently being tested in a large clinical trial with prasugrel (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes [TRILOGY ACS]; ClinicalTrials.gov Identifier: NCT00699998). The recent Canadian Cardiovascular Society Antiplatelet Therapy Guidelines 2010
      • Bell A.D.
      • Roussin A.
      • Cartier R.
      • et al.
      The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society Guidelines Executive Summary.
      recommend that in patients with ACS who undergo stent implantation and have an increased risk of stent thrombosis (eg, STEMI, history of diabetes, or prior documented stent thrombosis), prasugrel may be preferred over clopidogrel, in addition to ASA for 12 months. However, the recommendations state that prasugrel should be avoided in patients with an increased bleeding risk, likely to undergo CABG within 7 days, and with a history of stroke or transient ischemic attack (absolute contraindication). The 2011 ACC Foundation (ACCF)/AHA-focused unstable angina/NSTEMI update
      • Wright S.A.
      • Anderson J.L.
      • Adams C.D.
      • et al.
      2011 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction (updating the 2007 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      indicates that for patients aged > 75 years, or with weight < 60 kg, prasugrel had no net benefit and probably should only be used when there are other high-risk features (ie with diabetes or a history of prior MI), in which case, the net benefit appears to be greater.
      Ticagrelor is a nonthienopyridine, reversible direct platelet P2Y12 inhibitor not requiring metabolic activation, with a more rapid onset, and more pronounced platelet inhibition than clopidogrel. Ticagrelor is administered twice daily, whereas clopidogrel and prasugrel are administered once daily. In the PLATO study,
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      ticagrelor was superior to clopidogrel in patients across the spectrum of ACS, including NSTE-ACS patients and those not undergoing revascularization. Either ticagrelor 180 mg (followed by 90 mg twice daily), or clopidogrel 300 mg (followed by 75 mg daily) was administered at the time of randomization (11 hours after symptom onset and 4 hours after hospitalization), which was approximately 4 hours before coronary angiography. In contrast to the TRITON-TIMI 38 study evaluating prasugrel, in the PLATO study patients were allowed to have received clopidogrel prior to study drug randomization (46%), including up to a 600 mg load. Ticagrelor reduced recurrent ischemic events (CV death, MI, stroke) by 16% with no increase in major bleeding or the need for blood transfusion. There was a significant 21% reduction in CV mortality alone, as well as a reduction of in-stent thrombosis, balanced by a significant increase in non-CABG bleeding, and no difference in CABG-related bleeding. Ticagrelor was also superior to clopidogrel in patients undergoing either an invasive or a noninvasive strategy.
      • James S.K.
      • Roe M.T.
      • Cannon C.P.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial.
      Due to apparent “off-target” effects, ticagrelor was associated with an increased incidence of dyspnea. However, the dyspnea appears to be transient, self-limited in most cases, and benign (ie, unrelated to changes in cardiorespiratory function). For patients requiring early CABG, discontinuation of ticagrelor returns platelet aggregation to almost normal levels within 4-5 days, in comparison to 5-7 days with clopidogrel,
      • Gurbel P.A.
      • Bliden K.P.
      • Butler K.
      • et al.
      Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study.
      although levels of platelet inhibition remain significantly higher than with clopidogrel in the first 48 hours after stopping the antiplatelet agents. Ticagrelor therapy overcomes nonresponsiveness to platelet inhibition with clopidogrel, and its antiplatelet effect is the same in clopidogrel responders and nonresponders, as defined by various tests measuring platelet aggregation.
      • Gurbel P.A.
      • Bliden K.P.
      • Butler K.
      • et al.
      Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study.
      For NSTE-ACS patients, prasugrel use should be restricted to patients who have not received clopidogrel prior to coronary angiography and who require PCI. Ticagrelor, recently approved for use in Canada, is an attractive alternative to clopidogrel in high-risk patients with NSTE-ACS at the time of first medical contact, as was the case for nearly half the PLATO population. Furthermore, ticagrelor can be used in most ACS situations, except concomitantly with fibrinolysis where it has not yet been tested. However, provincial reimbursement varies widely and currently limits access to new agents such as prasugrel and ticagrelor for many Canadians. An initial Swedish analysis based on the PLATO study
      • Henriksson M.
      • Nikoloc E.
      • Janzon M.
      • et al.
      Long term costs and health outcomes of treating acute coronary syndrome patients with ticagrelor based on the EU label- Cost effectiveness analysis based on the PLATO study.
      showed treatment with ticagrelor compared with generic clopidogrel to be cost-effective. Ticagrelor was associated with a cost per quality-adjusted life years gained in the range of USD$3000-USD$8000 and cost saving when compared with proprietary clopidogrel.

      In-Hospital and Discharge Therapy

      Patients with ACS are at high risk for recurrent ischemic events especially in the first 30-45 days following their index event, but also over the long-term. Strategies for CV risk reduction with the aim of preventing recurrent ischemic events and heart failure must start early following an ACS. Lifestyle modification (smoking cessation, weight control, exercise, and diet) plays a crucial role in long-term management. Teaching is initiated and strategies discussed to achieve these adjustments while the patient is in-hospital. Referral to a cardiac rehabilitation clinic allows continued reinforcement and support for lifestyle change as well as optimization of treatment goals. The role of allied healthcare professionals including nurses, pharmacists, and dieticians is crucial not only for patient education, but also to ensure consistent adherence to discharge planning strategies.
      Medications for long-term risk reduction are shown in Table 13. In addition, blood pressure control and glycemic management remain important. For ACS patients with diabetes and established coronary artery disease, the target for glycemic control is HbA1c < 7%. Recommended blood pressure targets are < 140/90 for most patients and < 130/80 for patients with diabetes and/or chronic kidney disease. A recent study
      • Pitt B.
      • White H.
      • Nicolau J.
      • et al.
      Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure.
      suggests that influenza vaccine reduces major CV events in patients with ACS.
      Table 13In-hospital and/or discharge medications following ACS
      IndicationWarningsDurationControversial issues
      β-Blockers
      • Freemantle N.
      • Cleland J.G.
      • Young P.
      • et al.
      Beta blockade after myocardial infarction Systematic review and meta regression analysis.
      Most patients post ACS; especially with LV dysfunction or residual coronary stenoses
      • Signs of heart failure
      • Increased risk for cardiogenic shock
      • Age > 70 y
      • SBP < 120 mm Hg
      • HR > 100 or < 60 beats per min
      • PR > 0.24 s
      • Second or third degree heart block
      • Active asthma
      • Uncertain;
      • Up to 3 to 4 y based on clinical trial duration;
      • Indefinite with moderate to severe LV dysfunction
      Patients with unstable angina, post MI with normal LV and successful revascularization
      ASA
      • Cairns J.
      • Gent M.
      • Singer J.
      • et al.
      Aspirin, sulphinpyrazone or both in unstable angina: results of a Canadian multicentre trial.
      • Theroux P.
      • Waters D.
      • Qiu S.
      • et al.
      Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina.
      All patients with ACS unless contraindicatedAspirin allergy, peptic ulcerationLifetimeDose especially with higher dose clopidogrel
      Clopidogrel
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • et al.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      Most patients with ACS; alternatives are prasugrel or ticagrelor
      • Clopidogrel allergy (see text)
      • Platelet genetic polymorphisms
      • Interaction with PPI not conclusive: probably better to use pantoprazole
      • Post ACS no stent or BMS 12 mo
      • Post ACS DES at least 12 mo
      • More than 1 y duration with DES
      • Which patients should receive 600 mg loading dose
      Prasugrel
      • Wiviott S.D.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Prasugrel versus clopidogrel in patients with acute coronary syndromes.
      ACS patients. Prasugrel initiated after coronary anatomy definedAllergy (cross reacts with clopidogrel)12-15 moUp-front usage: as yet no supporting evidence
      Ticagrelor
      • Wallentin L.
      • Becker R.C.
      • Budaj A.
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      ACS patients (not post-thrombolysis)
      • Dyspnea
      • Ventricular pauses
      12 mo
      Statin
      • Baigent C.
      • Keech A.
      • Kearney P.M.
      • et al.
      Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
      • Cannon C.P.
      • McCabe C.H.
      • Wilcox R.G.
      • et al.
      Design of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)- TIMI 22 trial.
      • LaRosa J.C.
      • Grundy S.M.
      • Waters D.
      • et al.
      Intensive lipid lowering with atorvastatin in patients with stable coronary artery disease.
      ACS independent of lipid profileLifetimeDose of statin to maximize LDL reduction
      ACEi
      • Dagenais G.R.
      • Pogue J.
      • Fox K.
      • Simoons M.L.
      • Yusuf S.
      Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials.
      • Flather M.D.
      • Lonn E.M.
      • Yusuf S.
      Effects of ACE inhibitors on mortality when started in the early phase of myocardial infarction: evidence from the larger randomized controlled trials.
      • Hall A.S.
      • Murray G.D.
      • Ball S.G.
      Follow-up study of patients randomly allocated ramipril or placebo for heart failure after acute myocardial infarction: AIRE Extension (AIREX) study.
      • Yusuf S.
      • Sleight P.
      • Pogue J.
      • et al.
      Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients The Heart Outcomes Prevention Evaluation Study Investigators.
      • ACS patients with LVEF < 40%
      • Consider for all ACS patients to prevent recurrent MI
      • Hyperkalemia
      • Hypotension
      Lifetime
      • Agreement for LV protection
      • HOPE and EUROPA support use with normal LV function
      ARB
      • Yusuf S.
      • Teo K.
      • Anderson C.
      • et al.
      Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial.
      • McMurray J.
      • Solomon S.
      • Pieper K.
      • et al.
      The effect of valsartan, captopril, or both on atherosclerotic events after acute myocardial infarction: an analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT).
      ACS patients intolerant of ACEi with LVEF < 40%
      • Hyperkalemia
      • Hypotension
      LifetimeRoutine replacement of ACEi for vascular protection
      • Aldosterone
      •  antagonist
        • Pitt B.
        • White H.
        • Nicolau J.
        • et al.
        Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure.
      ACS with LVEF < 40%
      • Hyperkalemia
      • Hypotension
      LifetimeSpironolactone or eplerenone
      Influenza vaccine
      • Phrommintikul A.
      • Kuanprasert S.
      • Wongcharoen W.
      • et al.
      Influenza vaccination reduces cardiovascular events in patients with acute coronary syndrome.
      All ACS patientsAlmost negligibleYearlyLow use of vaccination and fear of adverse effects
      ACE, angiotensin converting enzyme; ACEi, ACE inhibitor; ACS, acute coronary syndromes; ARB, angiotensin receptor blocker; ASA, aspirin; BMS, bare-metal stent; DES, drug-eluting stent; EUROPA, European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease; HOPE, Heart Outcomes Prevention Evaluation study; HR, heart rate; LDL, low-density lipoprotein; LV, left ventricular; LVEF, LV ejection fraction; MI, myocardial infarction; PPI, proton pump inhibitor; SBP, systolic blood pressure.

      Funding Sources

      Publication of this article was supported by AstraZeneca Canada Inc. and Bristol-Myers Squibb Canada and sanofi-aventis Canada.

      Disclosures

      David Fitchett has received speaker honoraria from and served on advisory boards for Astra Zeneca, sanofi-aventis, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Servier, Boehringer Ingelheim, Abbott, and Roche.
      Pierre Theroux has served as a consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, and sanofi-aventis. Dr Theroux has also received speaker honoraria from AstraZeneca, Boeringher Ingelheim, Bristol-Myers Squibb, and sanofi-aventis, and he has received a research grant from Merck .
      James Brophy has no conflicts of interest to disclose.
      Warren Cantor has received speaker honoraria from and served on the advisory boards for AstraZeneca, Eli Lilly, and sanofi aventis.
      Jafna Cox has received speaker honoraria from AstraZeneca and served on advisory boards for AstraZeneca and Bristol-Myers Squibb/sanofi-aventis. Dr Cox has also had research funded by Pfizer, served as an expert consultant on the review of ticagrelor/Brillinta by the Canadian Agency for Drugs and Technologies in Health, and served as a scientific advisor to Cardiovascular Health Nova Scotia.
      Milan Gupta has received research grants and speaker honoraria from and served on advisory boards for AstraZeneca , Merck , Eli Lilly , Boehringer Ingelheim , sanofi-aventis , Roche , Servier , Abbott , and Bayer .
      Heather Kertland has received honoraria or consulting fees from sanofi-aventis, Astra Zeneca, and Eli Lilly.
      Shamir Mehta has served as an advisor or consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and sanofi-aventis. Dr Mehta has also received clinical trial funding from Astellas, Bristol-Myers Squibb, and sanofi-aventis.
      Robert Welsh has received research grant support from AstraZeneca , Boehringer Ingelheim , Bristol-Myers Squibb , Eli Lilly , Portola , and sanofi-aventis . Dr Welsh has also served as a consultant/advisory board member for or speaker honoraria from Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Medtronic, Roche, and sanofi-aventis.
      Shaun Goodman has received research grant support and/or honoraria for consulting/speaking from Actelion , AstraZeneca , Bayer , Boehringer Ingelheim , Bristol-Myers Squibb , Daiichi Sankyo , Eisai , Gilead , Glaxo Smith Kline , Johnson & Johnson , Kai Pharmaceuticals , Lilly , Merck , Novartis , Pfizer , Roche , sanofi-aventis , Servier , and The Medicines Company .

      Acknowledgements

      The authors acknowledge Elsevier Canada for allowing use and/or adaptation of content developed for inclusion in: Theroux P, Brophy J, Cox J, et al. Management of Non-ST Elevation Acute Coronary Syndromes: A Canadian Perspective on Current Guidelines. Toronto: Elsevier Canada, 2008.

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